Jonathon P. Fanning

The epidemiology of silent brain infarction: a systematic review of population-based cohorts.

BackgroundCerebral infarction is a commonly observed radiological finding in the absence of corresponding, clinical symptomatology, the so-called silent brain infarction (SBI). SBIs are a relatively new consideration as improved imaging has facilitated recognition of their occurrence. However, the true incidence, prevalence and risk factors associated with SBI remain controversial.MethodsSystematic searches of the Medline and EMBASE databases from 1946 to December 2013 were performed to identify original studies of population-based adult cohorts derived from community surveys and routine health screening that reported the incidence and prevalence of magnetic resonance imaging (MRI)-determined SBI.ResultsThe prevalence of SBI ranges from 5% to 62% with most studies reported in the 10% to 20% range. Longitudinal studies suggest an annual incidence of between 2% and 4%. A strong association was seen to exist between epidemiological estimates of SBI and age of the population assessed. Hypertension, carotid stenosis, chronic kidney disease and metabolic syndrome all showed a strong association with SBI. Heart failure, coronary artery disease, hyperhomocysteinemia and obstructive sleep apnea are also likely of significance. However, any association between SBI and gender, ethnicity, tobacco or alcohol consumption, obesity, dyslipidemia, atrial fibrillation and diabetes mellitus remains unclear.ConclusionsSBI is a remarkably common phenomenon and endemic among older people. This systematic review supports the association of a number of traditional vascular risk factors, but also highlights disparities between clinically apparent and silent strokes, potentially suggesting important differences in pathophysiology and warranting further investigation.

Characterization of Neurological Injury in Transcatheter Aortic Valve Implantation How Clear Is the Picture

The application of transcatheter aortic valve implantation (TAVI) to high-surgical-risk and inoperable patients with severe aortic stenosis (AS) is gaining widespread acceptance with a burgeoning supportive evidence base.1 The benefits associated with the application of this technique, however, are mitigated by the occurrence of major, disabling stroke with associated increased mortality and early-reduced quality of life.2 Despite this, the risk/benefit ratio has been considered acceptable in appropriately selected patients given the outcomes of alternate management options in these high-risk and inoperable populations.3,4 The incidence of cerebrovascular events (CVEs) subsequent to TAVI exceeds that after any other cardiac intervention or valve surgery, most notably in the acute periprocedural period, diminishing over the subsequent 2 months.5 This elevated early risk reflects the increased incidence of ischemic stroke thought secondary to particulate emboli dislodged by the procedure itself or as a result of thromboembolism.6 In fact, cerebral embolism is a universal finding associated with these procedures.7 Most events, however, are subclinical or silent, with clinically apparent CVEs representing but the tip-of-the-iceberg. As a result of the difficulty ascertaining these subclinical events, the true association between TAVI and neurological injury is unknown and the harm potentially underestimated. This article aims to comprehensively review neurological injury in TAVI, with an emphasis on cerebrovascular disease. Evidence and current concepts regarding pathophysiological mechanisms, risk factors, and prognostic implications will be discussed and risk reduction strategies explored. CVEs post-TAVI are classified based on clinical severity as illustrated in Figure 1. Incomplete reporting and variable definitions of clinically apparent events and disregard of subclinical events have limited the true evaluation of CVEs associated with TAVI. Consequently, in 2011 the Valve Academic Research Consortium published a consensus report on standardized end point definitions, including stroke, which were expanded and refined in …

Emerging Spectra of Silent Brain Infarction

Silent brain infarction (SBI) is an increasingly recognized, and yet still poorly understood, clinical disorder characterized by the often incidental finding of cerebral infarction on imaging in the absence of clinically apparent neurological deficit. Although first described ≈50 years ago by Fisher1 through autopsy studies, it was not until the development of more sensitive imaging modalities that their characterization has been possible. Of the epidemiological literature available on SBI, the most credible and generalizable data come from representative community samples, from which the general population prevalence of SBI has been estimated as 10% to 20%, with longitudinal studies suggesting a yearly incidence of 3% to 4%.2 However, this climbs as high as 55% in clinical-based studies of otherwise healthy patients3 and is higher than 90% in certain disease-specific populations.4 Despite such a high prevalence, mounting evidence suggests that SBI is not a silent event at all but is associated with subtle neurological deficits, neurocognitive dysfunction, psychiatric disorders, an increased incidence of overt stroke, and early mortality. In light of these associations, it has been proposed that the designation silent be replaced with the term covert.5 The principle objective of this article is to review the current body of published medical research critically to (1) define SBI and highlight problems inherent in that definition; (2) examine the risk factors, incidence and prevalence of SBI; (3) assess theories on the underlying pathogenesis of SBI; and (4) discuss the clinical consequences of these lesions. ### What Constitutes a SBI? There is no universally accepted definition of SBI, which hampers attempts to characterize and investigate these lesions fully. In general, SBI has been described as cerebral infarcts that are observed on either computed tomographic or MRI scans in the absence of any corresponding, clinically apparent cerebrovascular ischemic event.6 ### Problems in the Detection and Diagnosis of SBIs The rigor with which corresponding …

Transcatheter aortic valve implantation (TAVI): Valve design and evolution

The efficacy of transcatheter aortic valve implantation (TAVI) in high surgical risk and inoperable patients with severe aortic stenosis (AS) is rapidly gaining credibility with an ever-expanding body of supporting evidence. The potential of TAVI to be a treatment option for a significant cohort of patients with aortic stenosis has fuelled a drive for the optimum device and resulted in exponential advances in the technology with a focus on adverse event minimization and procedural simplification. Consequently, a plethora of new transcatheter valve choices are now available for clinical study or in the pipeline. The evaluation of past, current and emerging devices allows for an appreciation of the design considerations involved in this process and an insight to the future direction of the technology.

The janus faces of botulinum neurotoxin: Sensational medicine and deadly biological weapon

The botulinum neurotoxins are the most dangerous toxins known (BoNTs serotypes A–G) and induce profound flaccid neuromuscular paralysis by blocking nerve–muscle communication. Poisoned motoneurons react by emitting a sprouting network known to establish novel functional synapses with the abutting muscle fiber. Understanding how our motoneurons are capable of bypassing such transmission blockade, thereby overcoming paralysis, by an astonishing display of plasticity is one of the research goals that have numerous therapeutic ramifications. This Mini‐Review aims at giving a brief update on the recent discoveries regarding the molecular mechanism of botulinum toxins intoxication. Curing botulism still is a challenge once the toxin has found his way inside motoneurons. In view of the potential use of botulinum toxins as biological weapon, more research is needed to find efficient ways of curing this disease.

The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology

Extracorporeal membrane oxygenation (ECMO) is a technology capable of providing short-term mechanical support to the heart, lungs or both. Over the last decade, the number of centres offering ECMO has grown rapidly. At the same time, the indications for its use have also been broadened. In part, this trend has been supported by advances in circuit design and in cannulation techniques. Despite the widespread adoption of extracorporeal life support techniques, the use of ECMO remains associated with significant morbidity and mortality. A complication witnessed during ECMO is the inflammatory response to extracorporeal circulation. This reaction shares similarities with the systemic inflammatory response syndrome (SIRS) and has been well-documented in relation to cardiopulmonary bypass. The exposure of a patient’s blood to the non-endothelialised surface of the ECMO circuit results in the widespread activation of the innate immune system; if unchecked this may result in inflammation and organ injury. Here, we review the pathophysiology of the inflammatory response to ECMO, highlighting the complex interactions between arms of the innate immune response, the endothelium and coagulation. An understanding of the processes involved may guide the design of therapies and strategies aimed at ameliorating inflammation during ECMO. Likewise, an appreciation of the potentially deleterious inflammatory effects of ECMO may assist those weighing the risks and benefits of therapy.

The silent and apparent neurological injury in transcatheter aortic valve implantation study (SANITY): concept, design and rationale.

BackgroundThe incidence of clinically apparent stroke in transcatheter aortic valve implantation (TAVI) exceeds that of any other procedure performed by interventional cardiologists and, in the index admission, occurs more than twice as frequently with TAVI than with surgical aortic valve replacement (SAVR). However, this represents only a small component of the vast burden of neurological injury that occurs during TAVI, with recent evidence suggesting that many strokes are clinically silent or only subtly apparent. Additionally, insult may manifest as slight neurocognitive dysfunction rather than overt neurological deficits. Characterisation of the incidence and underlying aetiology of these neurological events may lead to identification of currently unrecognised neuroprotective strategies.MethodsThe Silent and Apparent Neurological Injury in TAVI (SANITY) Study is a prospective, multicentre, observational study comparing the incidence of neurological injury after TAVI versus SAVR. It introduces an intensive, standardised, formal neurologic and neurocognitive disease assessment for all aortic valve recipients, regardless of intervention (SAVR, TAVI), valve-type (bioprosthetic, Edwards SAPIEN-XT) or access route (sternotomy, transfemoral, transapical or transaortic). Comprehensive monitoring of neurological insult will also be recorded to more fully define and compare the neurological burden of the procedures and identify targets for harm minimisation strategies.DiscussionThe SANITY study undertakes the most rigorous assessment of neurological injury reported in the literature to date. It attempts to accurately characterise the insult and sustained injury associated with both TAVI and SAVR in an attempt to advance understanding of this complication and associations thus allowing for improved patient selection and procedural modification.

Neurological Injury in Intermediate‐Risk Transcatheter Aortic Valve Implantation

Background The application of transcatheter aortic valve implantation (TAVI) to intermediate‐risk patients is a controversial issue. Of concern, neurological injury in this group remains poorly defined. Among high‐risk and inoperable patients, subclinical injury is reported on average in 75% undergoing the procedure. Although this attendant risk may be acceptable in higher‐risk patients, it may not be so in those of lower risk. Methods and Results Forty patients undergoing TAVI with the Edwards SAPIEN‐XT ™ prosthesis were prospectively studied. Patients were of intermediate surgical risk, with a mean±standard deviation Society of Thoracic Surgeons score of 5.1±2.5% and a EuroSCORE II of 4.8±2.4%; participant age was 82±7 years. Clinically apparent injury was assessed by serial National Institutes of Health Stroke Scale assessments, Montreal Cognitive Assessments (MoCA), and with the Confusion Assessment Method. These identified 1 (2.5%) minor stroke, 1 (2.5%) episode of postoperative delirium, and 2 patients (5%) with significant postoperative cognitive dysfunction. Subclinical neurological injury was assessed using brain magnetic resonance imaging, including diffusion‐weighted imaging (DWI) sequences preprocedure and at 3±1 days postprocedure. This identified 68 new DWI lesions present in 60% of participants, with a median±interquartile range of 1±3 lesions/patient and volumes of infarction of 24±19 μL/lesion and 89±218 μL/patient. DWI lesions were associated with a statistically significant reduction in early cognition (mean ΔMoCA −3.5±1.7) without effect on cognition, quality of life, or functional capacity at 6 months. Conclusions Objectively measured subclinical neurological injuries remain a concern in intermediate‐risk patients undergoing TAVI and are likely to manifest with early neurocognitive changes. Clinical Trial Registration URL: http://www.anzctr.org.au. Australian & New Zealand Clinical Trials Registry: ACTRN12613000083796.

Intraoperative Cerebral Perfusion Disturbances During Transcatheter Aortic Valve Replacement

BACKGROUND Transcatheter aortic valve replacement entails profound and unavoidable hemodynamic perturbations that may contribute to the neurological injury associated with the procedure. METHODS Thirty-one patients were monitored with cerebral oximetry as a surrogate marker of perfusion while undergoing transcatheter aortic valve replacement via a transfemoral approach under general anesthesia to detect intraoperative hypoperfusion insult. Serial neurologic, cognitive, and cerebral magnetic resonance imaging assessments were administered to objectively quantify perioperative neurologic injury and ascertain any association with significant cerebral oximetry disturbances. RESULTS Cerebral oximetry reacted promptly to rapid ventricular pacing with significant cerebral desaturation, relative to baseline, of greater than 12% and greater than 20% in 12 of 31 (68%) and 9 of 31 (29%) patients, respectively; or to an absolute measurement of less than 50% in 10 of 31 (33%) patients. Hyperemia occurred immediately following relief of aortic stenosis exceeding baseline by greater than 10% and greater than 20% in 14 of 31 (45%) and 5 of 31 (16%) patients. Postoperative cognitive dysfunction was evident in 3 of 31 (10%) patients and new magnetic resonance imaging-defined ischemic lesions were seen in 17 of 28 (61%) patients. No patient experienced clinically apparent stroke. CONCLUSIONS Cerebral oximetry reacted promptly to rapid ventricular pacing with significant desaturation and hyperemia a common occurrence. However, no association between this intraoperative insult and objective neurologic injury was detected.

Neural network imaging to characterize brain injury in cardiac procedures: the emerging utility of connectomics

Cognitive dysfunction is a poorly understood but potentially devastating complication of cardiac surgery. Clinically meaningful assessment of cognitive changes after surgery is problematic because of the absence of a means to obtain reproducible, objective, and quantitative measures of the neural disturbances that cause altered brain function. By using both structural and functional connectivity magnetic resonance imaging data to construct a map of the inter-regional connections within the brain, connectomics has the potential to increase the specificity and sensitivity of perioperative neurological assessment, permitting rational individualized assessment and improvement of surgical techniques.